S130: PRELIMINARY RESULTS OF QUIWI: A DOUBLE BLINDED, RANDOMIZED CLINICAL TRIAL COMPARING STANDARD CHEMOTHERAPY PLUS QUIZARTINIB VERSUS PLACEBO IN ADULT PATIENTS WITH NEWLY DIAGNOSED FLT3-ITD WILD-TYPE AML

Topic: 4. Acute myeloid leukemia - Clinical Background: Inhibition of FLT3 and other kinases through oral targeted agents could improve standard chemotherapy outcomes for fit AML FLT3 wild type (WT) patients. The randomized SORAML trial from the SAL group, including FLT3-ITD mutated and WT, showed that the addition of type II inhibitor sorafenib improved leukemia-free, but not overall survival (OS) among newly diagnosed fit AML patients. Quizartinib (Quiz) is a potent type II inhibitor showing complete remissions (CR) as monotherapy for relapsed/refractory. With this rationale, the PETHEMA group designed a randomized, double-blind, placebo (PBO)-controlled phase II QUIWI trial (NCT04107727). Aims: The primary objective of QUIWI trial was to compare the event-free survival (EFS) (failure to achieve CR/CRi after 1 or 2 cycles, death in CR/CRi, or relapse, whichever occurs the first) between Quiz and PBO arms. We report here a preplanned interim analysis occurring 12 months after last patient inclusion. Methods: Multicenter, randomized, PBO-controlled, double-blinded phase II clinical trial. Patients with newly diagnosed FLT3-ITD WT AML, aged 18 to 70 years, and fit for intensive chemotherapy were centrally screened for FLT3-ITD prior to randomization. The trial was conducted in two phases: an open-label safety run-in phase exploring Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3), and Quiz 60 mg/d x 14 days to establish the dose for the randomized phase. The double-blinded phase 2:1 used randomization stratified by age (<60 vs. ≥60 years old) at diagnosis. A second identical induction cycle was allowed in case of failure to achieve CR/CRi after the first cycle. Consolidation (up to 4 cycles) consisted of high dose Cytarabine on Days 1, 3, and 5 plus Quiz or PBO for 14 days. Patients with high genetic risk or intermediate with MRD positivity were recommended for allo-SCT. A 12 cycles maintenance phase with 60 mg Quiz or PBO started after the consolidation or after allo-SCT. MRD monitoring, was performed through the PETHEMA centralized platform. NPM1 and CBF patients was assessed for MRD using RT-qPCR standardized techniques, and the remaining subgroups by standardized multiparametric flow cytometry. Results: From September 2019 to November 2021, 284 Pts were enrolled in 45 Spanish PETHEMA centers, 11 of them were included in the safety run-in phase establishing 60 mg/day of Quiz or PBO for the randomized phase. 273 Pts were randomized to Quiz (n=180) or PBO (n=93). The median age was 57 y [IQR, 48 – 64 y]. Baseline pts and disease characteristics were balanced between the 2 arms. At data cutoff (February 2023), the median follow-up was 17 months. Median EFS was 16.6 mo with Quiz vs 10.6 mo with PBO (hazard ratio [HR], 0.729; 95% CI, 0.522-1.018; 2-sided P=0.062) (Figure 1A). Regarding OS, 50 out of 180 patients died in the Quiz arm, and 45 out of 93 in the PBO. Median OS was not reached with Quiz vs 15 mo with PBO (HR, 0.558; 95% CI, 0.373-0.834; P=0.004), and the 2-years OS was 63.5% with Quiz vs 47% with PBO. (Figure1B). Disease-free survival was not reached with Quiz vs 15.4 mo with PBO (HR 0.643; 95% CI 0.411-1.005; P=0.050). CR/CRi rate after 2 cycles was 76.7% in the Quiz arm and 76.4% in the PBO. CR/CRi with MRD negativity after 2 cycles was achieved in 41.5% in the Quiz arm and 41.6% in the PBO. No new safety signals were observed among Quiz arm. Summary/Conclusion: Our study suggests that the addition of Quiz to 3 + 7 may prolong OS in newly diagnosed FLT3-ITD WT AML. A large biomarker plan to clarify underlying molecular mechanisms and final analyses with longer follow-up will be reported by the end of 2023.Keywords: flt3 inhibitor, Treatment, Clinical trial, Acute myeloid leukemia